Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/121—Solutions, i.e. homogeneous liquid formulation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins

Definitions

• the present disclosure relates to pharmaceutical composition with radiolabeled GRPR antagonist compound of high concentration and of high chemical and radiochemical stability that allows their use as commercial drug product for diagnostic and/or therapeutic purposes.
• GRP Gastrin-releasing peptide
• GRP GRP receptor
• GRPR G protein-coupled receptor originally isolated from a small cell lung cancer cell line.
• Upregulation of the pathway of GRP/GRPR has been reported in several cancers, including breast, prostate, uterus, ovaries, colon, pancreas, stomach, lung (small and non-small cell), head and neck squamous cell cancer and in various cerebral and neural tumours.
• GRPR overexpression can reach very high density according to tumour type (e.g. 70-90% expression in ductal breast cancer specimens) [Van de Wiele C, et al. J Nucl Med 2001, 42(11):1722-1727].
• GRPR are highly overexpressed in prostate cancer where studies in human prostate cancer cell-lines and xenograft models showed both high affinity (nM level) and high tumour uptake (% ID/g) but the relative expression of GRPR across evolving disease setting from early to late stage has not been fully elucidated yet [Waters, et al. 2003, Br J Cancer. June 2; 88(11): 1808-1816].
• GRP is physiologically present in pulmonary neuroendocrine cells and plays a role in stimulating lung development and maturation. However, it seems to also be involved in growth dysregulation and carcinogenesis. Stimulation of GRP leads to increasing the release of epidermal growth factor receptor (EGFR) ligands with subsequent activation of EGFR and mitogen-activated protein kinase downstream pathways.
• EGFR epidermal growth factor receptor
• NSCLC non-small cell lung cancer
• peptide receptor agonists have long been the ligands of choice for tracer development and utilization.
• the efficient receptor-mediated endocytosis in response to agonist stimulation provides high in vivo radioactivity uptake in targeted tissues, a crucial prerequisite for optimal imaging of malignancies.
• GRPR antagonists are safer clinical use, not so much at tracer doses for the current diagnostic point of view, but in view of greater doses for potential therapeutic purposes, as the use of antagonists does not foresee acute biological adverse effects [Stoykow C, et al. Theranostics 2016, 6(10):1641-1650].
• GRPR-antagonists like NeoB
• NeoB can be radiolabeled with different radionuclides and could potentially be used for imaging and for treating GRPR-expressing cancers, for example but not limited to, prostate cancer and breast cancer.
• the target cell receptor binding moiety is typically linked to a chelating agent which is able to form a strong complex with the metal ions of a radionuclide.
• This radiopharmaceutical drug is then delivered to the target cell and the decay of the radionuclide is then releasing high energy electrons, positrons or alpha particles as well as gamma rays at the target site.
• radiolysis the decay of the radionuclide occurs constantly, e.g. also during the manufacturing and during storage of the drug product, and the released high energy emissions induce the cleavage of the chemical bonds of the molecules which form part of the drug product. This is often referred to as radiolysis or radiolytic degradation.
• the radiolytic degradation of the receptor binding moiety of the drug may lead to a decrease in its efficacy to act as a diagnostic and/or therapeutic.
• the drug product may be stored at low temperatures, or produced in high dilution, or stabilizers may be added.
• Adding stabilizers however may be problematic as those chemicals may have a negative impact on the complexation of the radionuclide into the chelating agent or may have a limited solubility and precipitate from the solution. Ethanol has been reported as stabilizer against radiolysis (WO 2008/009444). While ethanol might not have a negative impact on the complexation or a solubility issue, higher amounts of ethanol in an infusion solution may be physiologically problematic and may have a negative impact on the tolerability of the drug product.
• the present inventors have now found a way to design and produce a highly concentrated radionuclide complex solution which is chemically and radiochemically very stable, even if stored at ambient or short term elevated temperatures so that it can be produced on commercial scale and supplied as ready-to-use radiopharmaceutical product.
• % has herein the meaning of weight percent (wt %), also referred to as weight by weight percent (w/w %).
• total concentration sum of one or more individual concentrations.
• aqueous solution a solution of one or more solute in water.
• the radionuclide metal ion is forming a non-covalent bond with the functional groups of the chelating agent, e.g. amines or carboxylic acids.
• the chelating agent has at least two such complexing functional groups to be able to form a chelate complex.
• Buffer for a pH from 4 to 6.0 may be an acetate buffer, citrate buffer (e.g. citrate+HCl or citric acid+Disodium hydrogenphosphate) or phosphate buffer (e.g. Sodium dihydrogenphosphate+Disodium hydrogenphosphate), preferably said buffer is an acetate buffer, preferably said acetate buffer is composed of acetic acid and sodium acetate.
• citrate buffer e.g. citrate+HCl or citric acid+Disodium hydrogenphosphate
• phosphate buffer e.g. Sodium dihydrogenphosphate+Disodium hydrogenphosphate
• Radionuclide metal ions preferably DTPA: Diethylentriaminepentaacetic acid.
• pH adjuster is chemical that is added to a solution to adjust a pH value of the solution and to thereby achieve a desired performance. Controlling the pH can be performed by adding a pH adjuster to the formulation.
• pH adjusters include commonly used acids and bases, buffers and mixtures of acids and bases.
• bases that can be used include NaOH, KOH, Ca(OH) 2 ), sodium bicarbonate, potassium carbonate, and sodium carbonate.
• acids that can be used include hydrochloric acid, acetic acid, citric acid, formic acid, fumaric acid, and sulfamic acid.
• the pH adjuster is a base, more preferably NaOH.
• the range of pH of the fluid can be any suitable range, such as about 2 to about 14.
• the drug product e.g. a pharmaceutical aqueous solution
• the drug product is able to obtain (preferably has obtained) marketing authorization by health authorities, e.g. US-FDA or EMA, by complying with all drug product quality and stability requirements as demanded by such health authorities, is able to be manufactured (preferably is manufactured) from or at a pharmaceutical production site at commercial scale followed by a quality control testing procedure, and is able to be supplied (preferably is supplied) to remotely located end users, e.g. hospitals or patients.
• the chelating agent in the context of the present disclosure may be
• DOTA 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid
• DTPA Diethylentriaminepentaacetic acid
• NTA Nitrilotriacetic acid
• EDTA Ethylenediaminetetraacetic acid
• DO3A 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid
• NOTA 1,4,7-Triazacyclononane-1,4,7-triacetic acid
• DOTA DOTA
• cell receptor binding moiety a chemical molecule which binds with at least part of its molecule to a receptor molecule at the surface of a cell.
• a cell receptor binding moiety for which the present disclosure is in particular suitable, is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, pasireotide, ilatreotide, pentetreotide, depreotide, satoreotide, veldoreotide, preferably selected from octreotide and octreotate.
• linking bond(s) is (are) either covalent or non-covalent bond(s) between the cell receptor binding organic moiety (and the linker) and the chelating agent, preferably the bond(s) is (are) covalent.
• “Stabilizer against radiolytic degradation” stabilizing agent which protects organic molecules against radiolytic degradation, e.g. when a gamma ray emitted from the radionuclide is cleaving a bond between the atoms of an organic molecules and radicals are formed, those radicals are then scavenged by the stabilizer which avoids the radicals undergoing any other chemical reactions which might lead to undesired, potentially ineffective or even toxic molecules. Therefore, those stabilizers are also referred to as “free radical scavengers” or in short “radical scavengers”. Other alternative terms for those stabilizers are “radiation stability enhancers”, “radiolytic stabilizers”, or simply “quenchers”.
• Radiochemical purity is that percentage of the stated radionuclide that is present in the stated chemical or biological form. Radiochromatography methods, such as HPLC method or instant Thin Layer Chromatography method (iTLC), are the most commonly accepted methods for determining radiochemical purity in the nuclear pharmacy.
• the terms “effective amount” or “therapeutically efficient amount” of a compound refer to an amount of the compound that will elicit the biological or medical response of a subject, for example, ameliorate the symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease.
• substituted or “optionally substituted” refers to a group which is optionally substituted with one or more substituents selected from: halogen, —OR′, —NR′R′′, —SR′, —SiR′R′′R′′′, —OC(O)R′, —C(O)R′, —CO 2 R′, —C(O)NR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′—C(O)NR′′R′′′, —NR′′C(O)OR′, —NR—C(NR′R′′R′′′) ⁇ NR′′′′, —NR—C(NR′R′′) ⁇ NR′′′ —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R′′, —NRSO 2 R′, —CN, —NO 2 , —R′, —N 3 ,
• alkyl by itself or as part of another substituent, refer to a linear or branched alkyl functional group having 1 to 12 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl).
• heteroaryl refers to a polyunsaturated, aromatic ring system having a single ring or multiple aromatic rings fused together or linked covalently, containing 5 to 10 atoms, wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O and S.
• the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
• Such rings may be fused to an aryl, cycloalkyl or heterocyclyl ring.
• Non-limiting examples of such heteroaryl include: furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl
• aryl refer to a polyunsaturated, aromatic hydrocarbyl group having a single ring or multiple aromatic rings fused together, containing 6 to 10 ring atoms, wherein at least one ring is aromatic.
• the aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl or heteroaryl as defined herein) fused thereto.
• Suitable aryl groups include phenyl, naphtyl and phenyl ring fused to a heterocyclyl, like benzopyranyl, benzodioxolyl, benzodioxanyl and the like.
• halogen refers to a fluoro (—F), chloro (—Cl), bromo (—Br), or iodo (—I) group.
• optionally substituted aliphatic chain refers to an optionally substituted aliphatic chain having 4 to 36 carbon atoms, preferably 12 to 24 carbon atoms.
• the present disclosure is described in further detail and is exemplified.
• ratio between gentisic acid and ascorbic acid is free acid concentration ratio ( ⁇ g/mL: ⁇ g/mL), i.e. concentration ratio with respect to GA and AA as free acids wherein the concentration of counter-ions, such as sodium (Na), is not taken into calculation.
• the present disclosure is concerned about a pharmaceutical composition, in particular a radiopharmaceutical composition.
• the pharmaceutical composition is for intravenous (IV) use/application/administration.
• IV intravenous
• the solution is stable, concentrated, and ready-to-use.
• the radiopharmaceutical composition according to the disclosure comprises:
• Said complex has the following formula:
• M is a radionuclide suitable for nuclear medicine
• C is a chelator which binds M
• S is an optional spacer covalently linked between C and the N-terminal of P
• P is a GRP receptor peptide antagonist, preferably of the general formula:
• Xaa1 is not present or is selected from the group consisting of amino acid residues Asn, Thr, Phe, 3-(2-thienyl) alanine (Thi), 4-chlorophenylalanine (Cpa), ⁇ -naphthylalanine ( ⁇ -Nal), ⁇ -naphthylalanine ( ⁇ -Nal), 1,2,3,4-tetrahydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (o-1-Tyr), Trp and pentafluorophenylalanine (5-F-Phe) (all as L- or D-isomers);
• Xaa2 is Gln, Asn or His
• Xaa3 is Trp or 1, 2, 3, 4-tetrahydronorharman-3-carboxylic acid (Tpi);
• Xaa4 is Ala, Ser or Val
• Xaa5 is Val, Ser or Thr;
• Xaa6 is Gly, sarcosine (Sar), D-Ala, or ⁇ -Ala;
• Xaa7 is His or (3-methyl)histidine (3-Me)His;
• Z is selected from —NHOH, —NHNH 2 , —NH-alkyl, —N(alkyl) 2 , and —O-alkyl or Z is
• X is NH (amide) or O (ester) and R1 and R2 are the same or different and selected from a proton, an optionally substituted alkyl, an optionally substituted alkyl ether, an aryl, an aryl ether or an alkyl-, halogen, hydroxyl, hydroxyalkyl, amine, amino, amido, or amide substituted aryl or heteroaryl group.
• Z is selected from one of the following formulae, wherein X is NH or O:
• P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z
• P is DPhe-Gln-Trp-Ala-Val-Gly-His-Z
• Z is selected from Leu- ⁇ (CH2N)-Pro-NH2 and NH—CH(CH 2 —CH(CH 3 ) 2 ) 2
• X is NH (amide) and R2 is (CH 2 —CH(CH 3 ) 2 and R1 is the same as R2 or different (CH2N)-Pro-NH2.
• the chelator C is obtained by grafting one chelating agent selected among the following list:
• M is a radionuclide suitable for nuclear medicine, selected from 111 In, 18 F, 211 At, 82 Rb, 123 I, 131 I, 133 mIn, 99 mTc, 94 mTc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As, 97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52 mMn, 157 Gd, 177 Lu, 161 Tb, 69 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117 mSn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr, 225 Ac, 43 SC, 44 Sc and 47 Sc.
• M is selected from 111 In,
• the chelator C is selected from the group consisting of DOTA, DTPA, NTA, EDTA, DO3A, NOC and NOTA, preferably is DOTA.
• S is selected from the group consisting of:
• PABZA p-aminobenzylamine
• PDA phenylenediamine
• PAMBZA (aminomethyl) benzylamine
• DIG diglycolic acid and IDA is iminodiacetic acid
• PEG spacers of various chain lengths in particular PEG spacers sele
• the GRPR antagonist is selected from the group consisting of compounds of the following formulae:
• P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH—CH(CH2CH(CH 3 ) 2 ) 2 .
• said complex is NeoB1 of formula (I):
• said complex is radiolabeled M-NeoB1 of formula (II):
• the radiolabeled GRPR-antagonist is radiolabeled NeoB2 of formula (III):
• M-N 4 p-aminobenzylamine-diglycolic acid-[D-Phe-Gln-Trp-Ala-Val-Gly-His-NH—CH[CH 2 —CH(CH 3 ) 2 ] 2 ; wherein M is a radonuclide.
• M is a radionuclide which can be selected from selected from, 111 In, 133 mIn, 99 mTc, 94 mTc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As, 97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52 mMn, 157 Gd, 177 Lu, 161 Tb, 69 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117 mSn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr, 225 Ac and 47 Sc.
• M is selected from 111 In, 177 Lu, 225 Ac and 68 Ga.
• M is 177 Lu.
• the radiolabeled GRPR-antagonist could be used for radionuclide therapy.
• M is 68 Ga.
• the radiolabeled GRPR-antagonist could be used for PET.
• M is 111 In.
• the radiolabeled GRPR-antagonist could be used for SPECT.
• the GRPR-antagonist is ProBOMB1 of the following formula (IV):
• the compounds of formula (I), (II), (Ill) and (IV) can be synthesized using the methods disclosed in the reference “ Positron Emission Tomography Imaging of the Gastrin - Releasing Peptide Receptor with a Novel Bombesin Analogue” ACS Omega 2019, 4, 1470-1478.
• the radiolabeled GRPR-antagonist has the tendency to degrade over time ending with radiochemical purity below the specifications at the end of the target shelf life (72 hours) which is a problem for formulating the pharmaceutical composition.
• the stability of the solution ascertained by the use of stabilizers against radiolytic degradation.
• stabilizer against radiolytic degradation refers to stabilizing agent which protects organic molecules against radiolytic degradation, e.g. when a gamma ray emitted from the radionuclide is cleaving a bond between the atoms of an organic molecules and radicals are forms, those radicals are then scavenged by the stabilizer which avoids the radicals undergo any other chemical reactions which might lead to undesired, potentially ineffective or even toxic molecules. Therefore, those stabilizers are also referred to as “free radical scavengers” or in short “radical scavengers”. Other alternative terms for those stabilizers are “radiation stability enhancers”, “radiolytic stabilizers”, or simply “quenchers”.
• the stabilizers used in accordance with the present inventions may be selected from gentisic acid (2,5-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium ascorbate), methionine, histidine, melatonine, ethanol, and Se-methionine.
• Preferred stabilizers are selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.
• Ethanol is considered as less preferred stabilizer due to tolerability issues associated with it if present in higher concentrations.
• Ethanol should be ideally avoided in the solutions of the present disclosure (in other words: free of ethanol), at least the amount of ethanol in the solutions of the present disclosure should be limited, e.g. less than 5%, preferably less than 2%, more preferably less than 1% in the final solution which is foreseen to be injected/infused. Even more preferably, the solution is free of ethanol.
• the present disclosure relates to a pharmaceutical composition
• a pharmaceutical composition comprising a radiolabeled GRPR-antagonist as described herein, and at least two stabilizers against radiolytic degradation.
• said at least two stabilizer can be selected from gentisic acid (2,5-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium ascorbate), methionine, histidine, melatonine, ethanol, and Se-methionine, preferably selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.
• Said at least two stabilizer can be gentisic acid or salts thereof and ascorbic acid or salts thereof.
• the inventors unexpectedly found that adding both ascorbic acid and gentisic acid in specific amounts in a pharmaceutical composition of a radiolabeled GRPR antagonist compound enables a radiochemical purity of said composition over 95% after 72 hours after synthesis.
• the ratio between gentisic acid and ascorbic acid is between 1:16 and 1:10, typically between 1:15 and 1:10, for example between 1:12 and 1:11.
• said gentisic acid or salts thereof can be present in a concentration of at least 1000 ⁇ g/mL, for example between 1000 ⁇ g/mL and 1500 ⁇ g/mL.
• said ascorbic acid or salts thereof can be present in a concentration of at least 10000 ⁇ g/mL, preferably at least 12000 ⁇ g/mL, preferably at least 15000 ⁇ g/mL, for example between 12000 and 18000 ⁇ g/mL.
• said gentisic acid or salts thereof is present in a concentration of least 1000 ⁇ g/mL, for example between 1000 ⁇ g/mL and 1500 ⁇ g/mL, and ascorbic acid or salts thereof is present in a concentration of 15000 ⁇ g/mL, for example between 12000 and 18000 ⁇ g/mL.
• the radiopharmaceutical composition comprises, as radiostabilizers, both gentisic acid and ascorbic acid, at the respective concentrations of 1312 ⁇ g/mL and 15000 ⁇ g/mL.
• the pharmaceutical composition has radiochemical purity higher than 95% up to 72 hours, preferably higher than 98% up to 72 h.
• the GRPR-antagonist has the tendency to stick to glass and plastic surfaces due to non-specific binding (NSB), which is a problem for formulating the pharmaceutical composition.
• NBS non-specific binding
• the present disclosure relates to a pharmaceutical composition
• a pharmaceutical composition comprising a radiolabeled GRPR-antagonist as described herein, at least two stabilizers against radiolytic degradation and optionally a surfactant.
• Said surfactant can comprise a compound having (i) a polyethylene glycol chain and (ii) a fatty acid ester.
• the surfactant also comprises free ethylene glycol.
• the surfactant comprises a compound of formula (V)
• n is comprised between 3 and 1000, preferably between 5 and 500, and more preferably between 10 and 50, and R is the fatty acid chain, preferably an optionally substituted aliphatic chain.
• the surfactant comprises polyethylene glycol 15-hydroxystearate and free ethylene glycol.
• said surfactant is a non-ionic surfactant.
• said non-ionic surfactant is selected from Macrogol 15 Hydroxystearate (Kolliphor HS 15), Poloxamer (Kolliphor P188), Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80) or Polyvinylpyrrolidone average mol wt 10,000 (Polyvinylpyrrolidone K10).
• said non-ionic surfactant is Macrogol 15 Hydroxystearate (Kolliphor HS 15).
• the radiolabeled GRPR-antagonist can be present in a concentration providing a volumetric radioactivity of at 370 MBq/mL (at EOP) ⁇ 37 MBq/mL ( ⁇ 10%)
• the surfactant can be present in a concentration of at least 5 ⁇ g/mL, preferably at least 25 ⁇ g/mL, and more preferably at least 50 ⁇ g/mL.
• the surfactant can be present in a concentration comprised between 5 ⁇ g/mL and 5000 ⁇ g/mL, preferably between 25 ⁇ g/mL and 2000 ⁇ g/mL, and more preferably between 50 ⁇ g/mL and 1000 ⁇ g/mL.
• the surfactant can be present in a concentration of 100 ⁇ g/mL.
• the present disclosure relates to a pharmaceutical composition
• a pharmaceutical composition comprising a radiolabeled GRPR-antagonist as described herein, at least two stabilizers against radiolytic degradation, optionally a surfactant and at least one other pharmaceutically acceptable excipient.
• the pharmaceutically acceptable excipient can be any of those conventionally used, and is limited only by physico-chemical considerations, such as solubility and lack of reactivity with the active compound(s).
• the one or more excipient(s) can be selected from buffer and/or solvent, and/or pH adjuster.
• Buffers include acetate buffer, citrate buffer and phosphate buffer.
• said buffer is acetate buffer.
• said solvents is water for injection.
• said pH adjuster is NaOH.
• the present disclosure relates to a pharmaceutical composition
• a pharmaceutical composition comprising a complex formed by radionuclide 177Lutetium (Lu-177), and NeoB of formula (I):
• gentisic acid or salts thereof and ascorbic acid or salts thereof Macrogol 15 Hydroxystearate, acetate buffer, water for injection, and NaOH.
• the pharmaceutical composition is an aqueous solution, for example an injectable formulation.
• the pharmaceutical composition is a solution for infusion.
• the disclosure also relates to the pharmaceutical composition as described above for use in treating or preventing cancer, typically GRPR-positive cancer.
• cancer refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth.
• Hyperproliferative and neoplastic disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state.
• pathologic i.e., characterizing or constituting a disease state
• non-pathologic i.e., a deviation from normal but not associated with a disease state.
• the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
• the cancer is selected from prostate cancer, breast cancer, small cell lung cancer, colon carcinoma, gastrointestinal stromal tumors, gastrinoma, renal cell carcinomas, gastroenteropancreatic neuroendocrine tumors, oesophageal squamous cell tumors, neuroblastomas, head and neck squamous cell carcinomas, as well as ovarian, endometrial and pancreatic tumors displaying neoplasia-related vasculature that is GRPR.
• the cancer is prostate cancer or breast cancer.
• the pharmaceutical composition is produced at commercial scale manufacturing, in particular is produced at a batch size of at least 0.5 Ci.
• the pharmaceutical composition is for commercial use.
• the disclosure also relates a pharmaceutical composition
• a pharmaceutical composition comprising a radiolabeled GRPR-antagonist, typically 177 Lu-NeoB, for use in treating or preventing cancer in a subject in need thereof, wherein said pharmaceutical composition is formulated with radiostabilizers as described in any of the previous embodiments, and is administered to said subject at a therapeutically efficient amount comprised between 2000 and 10000 MBq, typically with a radiochemical purity (RCP) superior to 95% at the time of administration.
• RCP radiochemical purity
• the subject is a mammal, for example but not limited to a rodent, canine, feline, or primate. In preferred aspects, the subject is a human.
• a therapeutically efficient amount of the composition is administered to said subject 2 to 8 times per treatment.
• a human patient may be treated with said pharmaceutical composition comprising a radiolabeled GRPR-antagonist, specifically 177 Lu-NeoB, administered intravenously in 2 to 8 cycles of a 2000 to 10000 MBq each, typically with radiochemical purity (RCP) superior to 95% at the time of administration.
• a radiolabeled GRPR-antagonist specifically 177 Lu-NeoB
• RCP radiochemical purity
• the 177 LuCl 3 may be obtained from commercial sources, e.g. I.D.B. Holland BV. All other components of the drug product are commercially available from various sources.
• Lu-NeoB manufacturing is performed automatically by using the MiniAlO synthesizer.
• the synthesis procedure has been developed as follows:
• the radiolabelling tests are carried out both manually and automatically by using the MiniAlO synthesizer.
• the synthesis procedure is developed as follows:
• the dilution solution is composed of ascorbic acid (antioxidant agent), DTPA (sequestering agent), NaOH (pH adjuster) and water for injection.
• LuNeoB has focused on the identification of the suitable amount of gentisic acid and ascorbic acid able to exert the desired protective function, without interfering in the labelling step.
• Example 2 Identification of the Suitable Formulation to Improve Radiochemical Purity of the Drug Product
• Antioxidants/free radical scavengers such as ascorbic acid and gentisic acid are typically used in radiopharmaceuticals preparation to protect the labelled molecules from radiolytic degradation.
• the radiochemical purity of drug product is higher than 95% up to 72 hours for the formulation containing at least 1000 ⁇ g/mL of gentisic acid and 10000 ⁇ g/mL of ascorbic acid.
• the tests carried out by increasing the ascorbic acid concentration show a clear improvement in the stability of the product at 15000 ⁇ g/mL (RCP % at end of shelf life >98%).
• the radiolabelling is carried out automatically by using the MiniAlO synthesizer.
• the synthesis procedure is developed as follows:
• the scale-up batches have been produced using the reaction buffer (product code F193,) and the formulation buffer (product code F191) produced by Gipharma and used for the production of Lutathera.
• the synthesis module is used to prepare the Drug Substance (Mother Solution) containing the 177 Lu-labelled molecule.
• the automatic synthesis process was developed to produce the radioactive Drug Substance as a sterile, aqueous concentrate mother solution.
• Drug Substance synthesis steps were set up in the MiniAlO (TRASIS) synthesizer module, a self-contained closed-system synthesis module which is automated and remotely controlled by GMP compliant software with monitoring and recording of the process parameters.
• MiniAlO TRASIS
• Mini AlO radiosynthesizer module is widely used in the radiopharmaceutical industry for manufacture of PET radiopharmaceuticals.
• This module incorporate a disposable fluid path which is preferred over fixed fluid path devices since it ensures a sterile and pyrogen free fluid path and eliminates the possibility of a cross-contamination between batches.
• the synthesis module is placed in a lead-shielded hot cell providing supply of Grade C HEPA filtered air.
• the isolator is inside a clean Grade C laboratory room.
• the sample VIAL-3 has been kept under agitation for the whole stability study.
• Table 11 summarizes the radiochemical purity results obtained for the 177 LuNeoB1 0.5 Ci scale-up batch. As it can be noted, the radiochemical purity of the product at t0 h meets the target specification being >97.00%.
• sample VIAL-4 The addition of the extra-amount of gentisic acid (sample VIAL-4) improves the stability of the finished product although the target shelf-life was not successfully met.
• VIAL-5 (6 mL sample) shows an improvement in terms of stability results compared to the 4 mL samples volumes despite the radiochemical purity at 72 h do not meet the specifications.
• the final amount of ascorbic acid and gentisic acid has been defined on the basis of the data collected during the development activities.
• the gentisic acid at a concentration of 1312 ppm together with the ascorbic acid at a concentration of 15000 ppm has shown excellent antioxidant properties allowing for the achievement of the target shelf life.
• the formulation selected for 177 LuNeoB manufacturing at a radioactivity level up to 500 mCi is the following:
• LuNeoB formulation Amount for 500 Component Purpose mCi synthesis 177 LuCl 3 acqueous Radioactive 500 mCi (1.5 mL) solution substance NeoB Active substance 600 ⁇ g Kolliphor HS 15
• NeoB Active substance 600 ⁇ g Kolliphor HS 15
• Tensioactive agent 100 ⁇ g/mL Gentisic acid Antioxidant agent 1312 ⁇ g/mL Ascorbic acid Antioxidant agent 15000 ⁇ g/mL
• Acetate buffer Buffer Qs DTPA Sequestering agent 370 ⁇ g/mL Water for injection Solvent Qs NaOH pH adjuster 4.77 mg/mL

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